Carbonyloxy steroids



United States Patent CARBONYLOXY STEROIDS John A. Hogg, Kalamazoo Township, and Jerome Korman, Portage Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan Application December 17, 1956 Serial No. 628,549

Claims. (Cl. 260397.45)

No Drawing.

This invention relates to steroid chemistry and is more particularly concerned withv novel 19-nor-1,3,5'(l0), 17-(20)-pregnatetraene-3,2l-diols of the formula CHzOH wherein R is selected from the group consisting of hydrogen, hydroxy, and keto.

This application is a continuation-in-part of our copending application Serial No. 406,364, now Patent No. 2,774,775, filed January 26, 1954.

It is an object of this invention to provide such novel compounds, as herein described, which are useful, for

example, in having estradiol-like activity and arefurther useful in the production of physiologically active steroid hormones having estradiol-like or adrenal cortical hormone activity. Illustratively, the 19-nor-1,3,5(10),17(20)- pregnatetraene-3,21-diols of the present invention are reduced by the Birch reaction to produce the A -3-keto group in theA ring. Esterification of the. 2l-hydroxy group with, for example, acetic anhydride, followed by the introduction of the l7a-hydroxy-20-keto group with hydrogen peroxide and a small amount of osmium tetroxide is productive of esters of'the physiologically active 10-normethyladrenal cortical hormones, e. g; 10- normethylcortisone acetate, 10-normethylhydrocortisone acetate, and 10-normethyl-1l-desoxyhydrocortisone. acetate, and the llu-hydroxy isomer of lO-norrnethylhydrocortisone acetate.

The 19-nor-l,3,5( 10) ,17(20) -pregnatetraene-3,21-diol compounds of the present invention, as illustrated by the foregoing structural formula, can be prepared by lithium aluminum hydride reduction of the corresponding alkyl 3-hydroxy-19-nor-1,3,5(10),17(20)pregnatetraen-21-oates as described in our copending application monoesters and 11,2l-diesters; l9-nor-l,3,5(l0),17'(20)- pregnatetraene-lafll-diol 3- and 21-monoesters and 3,21- diesters; 3-etherified 19-nor-1,3,5 (10),17(20)pregnatetraene-3,21-diol 2l-esters; 3,21-dihydroxy-19nor-1,3,5 (10), 17(20)-pregnatetraen-1l-one 3- and 2l-monoesters and 3,2l-diesters; and 3-etherified 3,21-dihydroxy-19-nor- 1,3,5 l0),17(20)-pregnatetraen-l1-one 2l-esters. Generally the etherified and esterified hydroxy groups each contain less than forty atoms. Preferably said groups are hydrocarbonoxy [hydrocarbon-O] and hydrocarboyloxy H [hydrocarbon-C-O] radicals, respectively, each containing less than twelve arbon atoms. In an especially preferred embodiment laid groups are alkoxy and alkanoyloxy radicals, respectively, each containing from one to eight carbon atoms, inclusive. The most preferred embodiment of said groups are methoxy and acetoxy, respectively. Illustrative etherified hydroxy groups are methoxy, ethoxy, propoxy, butyroxy, valeroxy, hexoxy, heptoxy, octanoxy, fi-trichloro-u-acetylethoxy, chloromethoxy, p-hydroxyethyleneoxy, dimethylmethoxy, diethylmethoxy, isobutyroxy, isovaleroxy, a-tetrahydropyranyloxy, 0c and p-naphthyloxy,

cyclohexyloxy, cyclopentyloxy, 5,5-dicarbethoxyethenyloxy, fl-keto-cyclohexenyloxy, a,fl-dimethylethoxy, 0:,5- and 5,}3-dicthylethoxy, benzoxy, ortho, meta and paratolyloxy, a and fi-phenylethyloxy, fi-indolyloxy, a-furyloxy, a and p-cyclohexylethyleneoxy, ortho, meta and para-nitrobenzoxy, ortho, meta and para-aminobenzoxy, etc. Illustrative esterified hydroxy groups are those containing acyl radicals of the acids formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, optically active abietic,

a-ethylisovaleric, cyclopropylideneacetic, 'cyclopentylformic, cyclopentylacetic, a and B-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, a and B-cyclohexylpropionic, benzoic, 2, 3 or 4-methylbenzoic, 2,3-, 2,4-,

.2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic,

2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic, S-methyl-a-naphthoic, phenylacetic, a and fl-phenylpropionic, diphenylacetic, triphenylacetic, succinic, glutaric, a-methylglutaric, fl-methylglutaric, fiLfi-dimethylglutaric,

. adipic, pimelic, suberic, glycolic, lactic, citric, tartaric,

3 -methyl-a-naphthoic, phenylacetic, a and flhphenylpropid-maleic, d-glyceric, malonic, gluconic, salicylic, glycine, diglycollamic, triglycollamic, methylglycine, dirnethylglycine, diethylglycine, para-aminosalicylic, para-aminobenzoic, ethylmercaptoacetic, benzylmercaptoacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic,thioglycolic, 2,3,4-trimethoxybenzoic, a-naphthoxyacetic, fl-pyrrolidylpropionic, carbamic acid, .phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarba-mic, allophanic, B-furylcarboxylic, N-methylpyrrolidyl- Z-carboxylic, wpicolinic, indoIe-Z-carboxylic, 6-hydroxy- 1 indolyl-3 -acetic, N-methylmorpholyl-Z-carboxylic, pyrrolyl-2-icarboxylic, etc.

The following examples are illustrative only and are not to be construed as limiting the scope of this invention.

. EXAMPLE 1 19-r z0r-J,3,5(10) ,1 7(20)-prcgnatetraene-3,1 fill-trial A solution of 300 milligrams of methyl 3,1lB-dihydroxy-l9-nor-1,3,5(l0),17(20)-pregnatetraen-2l-oate in ten milliliters of dry ether is added dropwiseat 26degrees Centigrade to a solution of 500 milligrams of lithium aluminum hydride in ten milliliterssof ether.

The resulting solution is stirred for 1.5 hours at room temperature and ten milliliters of ethyl acetate, followed Patented June 24, 1958 by fifteen milliliters of water are cautiously added'to the mixture to decompose the excess lithium aluminum hydride. The mixture is made slightly acidic at zero degrees centigrade with dilute hydrochloric acid and then extracted thoroughly with ether. The ether extracts are combined, dried and the solvent distilled to leave a residue of 19-nor-l,3,5(l0),17*(20)-pregnatetraene-3,l1,3,21- triol. Recrystallized from ethyl acetate the compound melts at 196 to 198 degrees centigrade.

EXAMPLE 2 19-n0r-I,3,5(10) ,17(20) -pregnatetraene-3,11,6,21-triol A pyrolysis tube of 2.5-centimeter diameter hard glass (Vycor) is mounted vertically and packed with one-millimeter diameter and five-millimeter long hard glass (Vycor)' rings, and a thirty-centimeter length of the pyrolysis tube is heated by a combustion furnace. The infiuent liquid is forced by nitrogen gas under pressure from a reservoir through a flowmeter into the pyrolysis tube. The efiluent gases and liquid are collected in a receiver cooled in ice and vented to an exhaust system. Reaction temperatures are measured by a thermocouple mounted inside the tube immediately outside of the heated zone exit, providing the temperature of the eflluent liquid, and a thermocouple mounted between the pyrolysis tube and the furnace. A suspension of twenty grams of 11 3, 2l-dihydroxy-1,4,l7(20)-cis-pregnatrien 3 one in two liters of heavy mineral oil is prepared by efiicient mixing (Waring blender. for fifteen minutes), and the suspension is passed through the pyrolysis tube at a rate of ten milliliters per minute maintaining the temperature of the effluent liquid at 400 degrees centigrade, the thermocouple between the pyrolysis tube and the furnace reading 650 degrees centigrade. After completion of the pyrolysis reaction, the cooled eflluent liquid is extracted with five percent aqueous sodium hydroxide solution, the extract acidified with dilute aqueous hydrochloric acid, and'the acidified aqueous solution extracted with methylene chloride. Distillation of the methylene chloride gives eight grams of solid. This solid is chromatographed over 640 grams of magnesium silicate (Florisil). Using 1:4 acetone-hexane (Skellysolve B) mixture as the solvent provides 4.8 grams of solid. Recrystallization of this solid from ethyl acetate provides 2.9 grams of purified 19- nor-l,3,5(10) ,l7(20)-pregnatetraene-3,115,21-triol; melting point 197 to 199 degrees centigrade. A sample further recrystallized from methanol for analytical purposes melts at 199.5 to 202 degrees centigrade; lab is plus 110 degrees in acetone.

Analysis.-Calculated for C H O C, 76.40; H, 8.44. Found: C, 76.62; H, 8.66.

EXAMPLE 3 3-methoxy-19-nor-1 ,3,5 (10) ,1 7(20) -pregnat etraene- 115,21-di0l A solution of 7.7 grams of 19-nor-1,3,5(10),17(20)- pregnatetraene-3,115,21-triol and .33 grams of potassium hydroxide in 170 milliliters of water is prepared and eleven 4-milliliter portions of dimethyl sulfate is added, with stirring, at fifteen-minute intervals. The crude solid product is isolated by filtration. The solid is chromatographed over magnesium silicate (Florisil) using acetonehexane (Skellysolve B) solvent to provide 4.5 grams of 3- methoxy-19-nor-1,3,5 10),17 (20) -pregnatetraene-1 113,21- diol. Recrystallization of the product from ethyl acetate provides 3.9 grams ofpurified product; melting point 141 to 144 degrees centigrade. Further recrystallized the product melts at143 to 144 degreescentigrade; [M is plus 122 degrees in chloroform.

Analysis-Calculated for C H O C, 76.79; H, 8.59. Found: C. 76.94; H, 8.74.

By substituting diethyl sulfate for the dimethyl sulfate in the foregoing procedure 3-ethoxy-19-nor-1,3,5(10),l7'

(20) pregnatetraene-l119,21 -dio1 is prepared. In place of the dialkyl sulfate, other etherifying agents can be employed, e. g. the paratoluenesulfonic acid ester of an alcohol, according to prior art procedure. In the same manner other S-ethers are prepared from the 3-hydroxysteorid and the appropriate esterifying agent, including 3-benzyloxy-, 3-propoxy-, 3-(/3-hydroxyethoxy)-, 3-butyroxy-, 3- (fi,fl-diethylethoxy)-, 3-(B-methoxyethoxy)-, 3-(a-naphthoxy)-, 3-(a-furyloxy)-, 3-isovaleroxy-, 3-cyclohexyloxy-, 3-benzoxy, 3-octanoxy-, and 3-(fi-phenylethoxy)-l9-nor- 1,3,5 (10) ,17(20)-pregnatetraene-l 16,2l-diol, and other 3-ethers of l9-nor-l,3,5(l0),l7(20)-pregnatetraene-3,l1B, 21-triol wherein the 3-etherified hydroxyl groups include those named in the foregoing description.

EXAMPLE 4 3-meth0xy-I1;3,21-diacet0xy-19-n0r-1,3,5 (10) ,17(20) pregnatetraene Acetylation of 2.82 grams of 3-methoxy-19-nor-1,3,5 (l0),17(20)-pregnatetraene-1118,2ldi0l by warming with twenty milliliters of acetic anhydride and twenty milliliters of dry pyridine, and then chromatographing the product over magnesium silicate (Florisil) using acetonehexane (Skellysolve B) mixture for elution, gives 3.17 grams of 3-rnethoxy-l 16,21-diacet0xy-l9-nor-1,3 ,5 10) l7 20 -pregnatetraene.

In the same manner other 11t3,2l-diestcr compounds are prepared from the 3-etherified 19-nor-1,3,5(10),17 (20)-pregnatetraene3,11,6,21-tri0ls of Example 2 by reaction with the appropriate acid chloride or acid anhydride, including 3-eth0xy-llB,2l-dipropionyloxy-, 3-benzoxy- 11fl,2l-diisovaleryloxy-, 3-octanoxy-l1,6,21-di-(trimethylacetoxy) 3- (fl-hydroxyethoxy -l 1,6,21-di- {B-cyclopentylpropionyloxy) -3-cyclohexyloxy-1 1,8,21-dibenzoyloxy-, and 3-methoxy-11fi,21-di-(a-furoyloxy)-l9 nor l,3,5(10), l7(20)-pregnatetraene, and other 115,2l-diesters of the 3- etherified 19-nor-1,3,5( 10) ,17 (20)-pregnatetraene-3, l 16, 21-triols of Example 2 wherein the and 2l-esterified hydroxyl groups include those named previously in the description.

EXAMPLE 5 3,115,21-triacet0xy-19-n0r-1,3,5 10 ,1 7 (20) -pregnatetraene Acetylation of 610 milligrams of 19-nor-1,3,5(10),17 (20)-pregnatetraene-3,115,2l-triol with acetic acid in pyridine according to the procedure of Example 3 gives 660 milligrams of 3,115,2l-triacetoxy-19-nor-1,3,5(10), l7(20)-pregnatetraene which is purified by chromatographing over magnesium silicate (Florisil) using acetonehexane (Skellysolve B) mixture for elution.

In the same manner other 3,113,21-triester compounds are prepared from 19-nor-1,3,5(10),17(20)-pregnatetraene-3,11;3,21-triol by reaction with the appropriate acid chloride or acid anhydride, including 3,115,21-tributyryloxy-, 3,1lfi,2l-tri(phenylacetoxy)-, 3,l1fl,2l tri (paratoluoyloXy)-, 3,11 9,2l-tricyclohexanoyloxy-, and 3,115, 21-tri-(fl-furylcarbonyloxy)-19 nor l,3,5(l0),l7(20)- pregnatetraene, and other 3,115,2l-triesters of l9-n0r-l, 3,5 (10),17(20)-pregnatetraene-3,1 15,21-triol wherein the 3,1113 and 2l-esterified hydroxyl groups include those named in the foregoing description.

EXAMPLE 6 3,2I-diacet0xy-19-n0r-1,3,5 (10 ,17 (20)-pregnatetraen- 1 Ifl-ol A solution of 200 milligrams (0.638 millirnole) of i9- nor-1,3,5( 10) ,17(20)-pregnatetraene-3,l 1,9,2 l-triol, three milliliters of pyridine, and 0. 13 milliliter (1.4 millimoles) of acetic anhydride is maintained at a temperature of 25 degrees centigrade' for seventeen hours. The solution then isdiluted with methylene dichloride and washed well with dilute aqueous hydrochloric acid solution. The

washed methylene dichloride solution is dried over anhydrous sodium sulfate and then chromatographed over fifteen grams of magnesium silicate (Florisil) using mixtures of hexane (Skellysolve B) and acetone for elution.

After evaporation of the solvent, a 176-milligram sample EXAMPLE 7 19-nor-1,3,5(I0) ,17(20) -pregnatetraene- 3,11u,21-triol An ether solution of 3,11u-dihydroxy 19 norl,3,5(),17(20)-pregnatetraen-2l-oate is reduced with lithium aluminum hydride in ether to produce l9-nor- 1,3,5 10) ,l7(20) -pregnatetraene-3,1 loz,2l-tl'i0l following the procedure of Example 1 for the reduction of the corresponding llfi-hydroxy compound.

'EXAMPLE 8 19-nor-1,3,5 10) ,1 7(20) -pregnatetraene-3,21-di0l 3-hydroxy-19-nor-1,3,5(l0),17(20) pregnatetraen-Zloate is reduced with lithium aluminum hydride in ether solution, following the procedure of Example 1 for the reduction of the corresponding llfl-hydroxy substituted compound, to produce 19-nor-1,3,5(l0),l7(20)-pregnatetraene-3,21-diol.

' EXAMPLE 9 3,21-dihydroxy-I9-n0r-1,3,5(10),17(20)- pregnatetraen-II-one A suspension of 2l-hydroxy-1,4,l7(20)-cis-pregnatriene-3,l1-dione in heavy mineral oil is pyrolyzed to produce 3,21-dihydroxy-l9-nor-1,3,5(10),17(20)- pregnatetraen-ll-one following the procedure of Example 2 for the pyrolysis of the corresponding llp-hydroxy compound. g n I 3,21 dihydroxy l9 nor 1,3,5(10),17(20) pregnatetraen-ll-one also is produced by oxidation of 3,21- diacetoxy-19-nor-l,3,5 10) ,17(20) pregnatetraen-l -01 with chromic acid in acetic acid solution at room temperature (between about twenty and about thirty degrees centigrade) to produce 3,21-diacetoxy-l9-nor-1,3,5(l0),- l7(20)-pregnatetraen-1l-one, followed by hydrolysis of the 3 and 2l-acetate ester groups with sodium carbonate in methanol solution at room temperature to produce 3,21-dihydroxy-l9-nor-1,3,5(10),l7(20) pregnatetraen- 11-one.

EXAMPLE 10 19- nor-1 ,3,5(10),17(20) '-pre gnatetraen-3,2l-di0l Following the procedure; of Example 2 for the conversion of 115,21-dihydroxy 1,4,17()-cis-pregnatrien 3 one to l9-nor-l,3,5(10),17(20)-pregnatetraene-3,11,8,21-

triol, 21 hydroxy-l,4,l7(20) cis-pre gnatrie'n-3-one is pyrolyzed to produce 19-no'r- 1, 3,5(l0),l7(20)-pregnatetraene-3,21-diol identical with the compound of Example 8. i

EXA PLE 11 19-n0r-1,3,5 (10) ,17(20) -pfegnatetr2zene-3,11a,21-tri0l In exactly the same manner as the corresponding 11 8- hydroxy compound is pyrolyzed inExample 2, 110:,21- dihydroxy-1,4,l7(20)-cis-pregnat1ien-3-one is pyrolyzed to produce 19 nor 1,3,5 l0),17 (20)-pregnatetraene- 3,1lu,2l-triol identical with the compound of Example 7.

EXAMPLE 12 3- meth0xy-19-n0r-1,3,5 (1 0 ,1 7 (20) -pregnatetraene- 11 4,21 -di0l An aqueous solution of l9-nor-1,3,5(10),l7(20)-pregnatetraene-3,l1a,21-triol containing potassium hydroxide is prepared and dimethyl sulfate is added with stirring, following the etherification procedure of Example 3. The crude solid product is isolated by filtration. The solid is chromatographed over magnesium silicate (Florisil) using acetone-hexane (Skellysolve B) solvent to provide 3- methoxy 19 nor 1,3,5(10),17(20) pregnatetraene- 11u,21-diol.

By substituting diethyl sulfate for the dimethyl sulfate in the foregoing procedure 3-ethoxy-19-nor-l,3,5(10),- 17(20)-pregnatetraene-lla,21-diol is prepared. In place of the dialkyl sulfate, other etherifying agents can be employed, e. g. the para-toluenesulfonic acid ester of an alcohol, according to prior art procedure. In the same manner other S-ethers are prepared from the B-hydroxysteroid and the appropriate esterifying agent, including 3- benzyloxy-, 3-propoxy-, 3-(fl-hydroxyethoxy)-, 3-butyr oxy-, 3-(fl,p-diethylethoxy)-, 3-(fi-methoxyethoxy)-, 3- (a-naphthoxy)-, 3-(u-furyloxy)-, 3-isovaleroxy-, 3-cyclohexyloxy-, 3-benzoxy-, 3-octanoxy-, and 3-(13-phenylethoxy)-19-nor1,3,5(10),17(20)-pregnatetraene ;,21- diol, and other 3-ethers of 19-nor-1,3,5(10),17(20)-pregnatetraene-3,l 1a,21-trio1 wherein the B-etherified hydroxyl groups include those named in the foregoing description.

EXAMPLE 13 3-meth0xy-11 1:,21-diacetoxy-19-nor-I,3,5 (10),] 7(20) pregnatetraene Acetylation of 3 methoxy-l9-nor-l,3,5(l0),17(20)- pregnatetraene-l10:,21-di0l by warming With acetic anhydride and dry pyridine, according to the esterification procedure of Example 4, and then chromatographing the product overmagnesium silicate (Florisil) using acetonehexane 1(Skellysolve B) mixture for elution, gives 3- methoxy 110;,21 diacetoxy-19-nor-l,3,5(l0),17(20)- pregnatatraene.

In the same manner other l1a,21-diester compounds are prepared from the 3-etherified l9-nor-1,3,4,(10),- 17(20)-pregnatetraene-3,l1a,21 trio1s of Example 12 by reaction with the appropriate acid chloride or acid anhydride, including 3-ethoxy-1la,2l-dipropionyloxy-, 3-benzoxy-lla,2l-diisovaleryloxy-, 3-octanoxy lla,21-di-(trimethylacetoxy)-, 3-(5 -'hydroxyethoxy) 11a,2l-di-(pcyclopentylpropionyloxy)-, 3-cyclohexyloxy llu,21-dibenzoyloxy-, and 3-methoxy-1la,2l-di-(u-furoyloxy)-l9- nor-1,3,5(10),17(20)-pregnatetraene, and other 110:,21- diesters of the S-etherified 19-nor-l,3,5(10),17(20)- pregnatetraene-3,l1a,21-triols of Example 12 wherein the 11aand 2l-esterified hydroxyl groups include those named previously in the description.

EXAMPLE 14 3,11 a,21-triacet0xy-19-nor-1,3,5 (10) ,1 7 (20) pregnatetraene Acetylation of l9-norl,3,5 10 1 7 (20 -pregnatetraene- 3,l1a,21-triol with acetic acid in pyridine according to the procedure of Example 4 gives 3,l1a,2l-triacetoxy-19- nor-l,3,5(10),l7(20)-pregnatetraene which is purified by chromatographing over magnesium silicate (Florisil) using acetone-hexane (Skellysolve B) mixture for elution.

1,3,5 ),17 (20) -pregnatetraene 3,11a,21 triol wherein the 3,110: and 21-esterified hydroxyl groups include those named inthe foregoing description.

EXAMPLE 3,21 -diacetoxy-1 9-nor-1,3,5 (10),] 7 -pregnatetmen-11 a-ol A solution of 19 nor l,3,5('l0),l7(20) pregnatet raene-3,lla,2l-triol, pyridine, and acetic anhydride is maintained at a temperature of degrees centigrade for sixteen hours. The solution then is diluted with methylene dichloride and washed well with dilute aqueous hydrochloric acid solution. The washed methylene dischloride solution is dried over anyhdrous sodium sulfate and then chromatographed over magnesium silicate (Florisil) using mixtures of hexane (Skellysolve B) and acetone for elution. After evaporation of the solvent 3,21- diacetoxy 19 nor -1,3,5(10),17(20)- pregnatetraen-lla-ol is obtained. The material is crystalized from methanol to achieve further purification.

In the same manner are prepared other 3,21-diesters of l9-nor-1,3,5(10),17(20) pregnatetraene 3,11a,21 triol and 2l-esters of the 3-etherified l9-nor-1,3,5(10),17(20)- pregnatetraene-3,11a,21-triols of Example 12, including those wherein the esterified hydroxyl groups are those named in the description and previous examples.

EXAMPLE 16 3-meth0xy-2I -hydr0xy-1 9-n0r-1,3,5 (1 0) ,1 7(20 pregnatetraen-I I -one An aqueous solution of 3,21dihydroxy-19-nor-1,3,5 (10),17(20)-pregnatetraen 1l-one containing potassium hydroxide-is prepared and dimethyl sulfate is added with stirring, following the etherification procedure of Example 3. The crude solid produet is isolated by filtration. The solid is chromatographer" over magnesium silicate (Florisil) using acetone-hexane (Skellysolve B) solvent to provide 3-methoxy 21 hydroxy 19,- nor 1,3,5 (10),'

3 butyroxy-, 3 (13,;3-diethylethoxy)-, 3 (fl-methoxyethoxy)-, 3-(a-naphthoxy 3-(a-fury1oxy)-, 3-isovaleroxy-, 3-cyclohexyloxy 3-benzoxy, 3-oetanoxy-, and 3-(fi-phenylethoxy)-2l'-hydroxy-19 nor 1,3 ,5(l0),17(20)-pregnatetraen-ll-one and other '3-ethers of 3,2l-dihydroxy-l9- nor-1,3,5(10),17(20)-pregnatetraen-ll-one wherein the 3-etherified hydroxyl groups include those named in the foregoing description.

EXAMPLE 17 3 -methoxy-21 -acetaxy-1 9-n0r-1 ,3 ,5 (1 0),] 7(20) pregnatetraen-I 1 -one Acetylation of 3-methoxy-2l-hydroxy-19-nor-1,3,5 10) l7(20).-pregnatetraen-,ll-one by warming with acetic anhydride and dry pyridine, according to the esterification procedure of Example 4, and then chromatographing the product over magnesium silicate (Florisil) using acetone-hexane (Skellysolve B) mixture for elution, gives 3-methoxy-21-acetoxy-l9 nor l,3,5(10),17 (20)-pregnatetraen-l1-one.

A solutionof 3,2l-dihydroxy-19 nor-1,3,5(10),17(20)- pregnatetraen-ll-one,pyridine, and acetic anhydride is maintained at a temperature of 25 degrees Centigrade for sixteen hours. The solution then is diluted with methylene dichloride and washed well with dilute aqueous hydrochloric acid solution. The washed methylene dichloride solution is dried overanhydrous sodium sulfate and then chromatographed over magnesium silicate (Florisil) using mixtures of hexane (Skellysolve B) and acetone for elution. After evaporation of the solvent, 3,21-diacetoxy-l9 nor 1,3,5(10),17(20)-pregnatetraenll-oue is obtained.

ExxMPLs 19 3,21-diacetoxy-19-nor-1,3,5(10),17(20)- pregnatetraene Acetylation of 19-nor-1,3,5(10),17(20)-pregnatetraene- 3,2l-diol with .acetic acid in pyridine according to the procedure of Example 4 gives 3,21-diacetoxy-19-nor- 1,3,5 10),17(20) -pregnatetraene which is purified by chromatographing over magnesium silicate (Florisil) using acetone-hexane (Skellysolve B) mixture for elution.

In the same manner ,other 3,21-diester,compounds are prepared from 19-nor-1,3,5(10),17(20)-pregnatetraene- 3,21-dial by reaction with the appropriate acid chloride or acid anhydride, including 3,21-dibutyryloxy-, 3,21-di- (phenylacetoxy) 3,2l-di-(para-toluoyloxy-, 3,2l-dicyclohexanoyloxy-,' and 3,21-di-(fl-furylcarbonyloxy)-19-nor- 1,3,5 (l0),l7(20)-pregnatetraene, and other 3,2l-diesters of 19 nor 1,3,5(10),17(20) pregnatetraene 3,21-diol wherein the 3 and ZI-esterified hydroxyl groups include those named in the foregoing description.

It is to be understood that the invention is not to be limited to the exact details or exact compounds shown and described as obvious modifications and equivalents will be apparent 'to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 19-nor-1,3,5(10),17(20)-pregnatetraene 3,21 diols of the formula CHIOH wherein R is selected from the group consisting of hydrogen, ,hydroxy, and keto.

2. l9-nor-1,3,5 (10) ,17 (20) pregnatetraene 3,21-diol.

3. 19-nor- 1,3,5 (10),17(20) pregnatetraene 3,115,21- triol.

4. 19-nor-1,3,5(10),l7(20) pregnatetraene 3,1 1:1,21-

triol.

5. 3,2l-dihydroxy-l9-uor-1,3,5(10),17(20). preguatetraen-l l-one.

References Cited in the file of this patent UNITED STATES PATENTS 2,774,775 Korman Dec. 18, 1956 

1. 19-NOR-1,3,5(10),17(20)-PREGNATETRAENE- 3,21 - DIOLS OF THE FORMULA 